Alkaloids are plant metabolites that have a nitrogen-containing chemical ring structure, alkali-like chemical reactivity, and pharmacologic activity.[1] The alkaloids represent a very diverse group of medically significant compounds that include well-known drugs like the opiates.
A subgroup of the alkaloids is the alkaloid amines. The three major pharmacologic groups of alkaloid amines are the hallucinogenic alkaloid amines, the stimulant alkaloid amines, and the highly anticholinergic tropane alkaloids (also called the belladonna alkaloids or bicyclic alkaloids).[2]
Plants that contain the tropane alkaloids atropine, scopolamine, and hyoscyamine include the following:
Datura species (jimson weed, angel's trumpet, thorn apple)[3, 4]
Hyoscyamus niger (henbane)
Atropa belladonna (deadly nightshade)[5, 6]
Mandragora officinarum (mandrake)
All of these plants have long histories of hallucinogenic use and have been connected with sorcery, witchcraft, native medicine, and magico-religious rites dating back to 1500 BC and Homer's Odyssey. (Homer's use of the plant moly as an antidote to Circe's poisonous anticholinergic drugs may have been the first recorded use of an anticholinesterase to reverse central anticholinergic intoxication.)
Chinese herbal medicines containing tropane alkaloids have been used to treat asthma, chronic bronchitis, pain, and flu symptoms. In Mexico, Datura (see the images below) is taken by Yaqui women to lessen pain of childbirth. In Africa, a common use is to smoke leaves from Datura to relieve asthma and pulmonary problems. Many cultures worldwide add plants with tropane alkaloids (particularly Datura species) to alcoholic beverages to increase intoxication.
Recently, Datura has been used as a recreational hallucinogen in the United States, resulting in sporadic cases of anticholinergic poisoning and death. Among the most commonly reported desired effects, euphoria, surreal interactions with world, and auditory hallucinations have been frequently reported by recreational users. After oral intake, the effects may arise in around 20-30 minutes, depending on the dose; if smoked, the effects are faster (around 5 minutes). After the intake of moderate doses, the effects last approximately 8-12 hours; with higher doses, effects may last 2-3 days.[7]
Long-term consumption of Datura resulting in the onset of paranoid schizophrenia, an altered state of consciousness, and aggressive behaviour has been reported.[8]
Numerous cases of anticholinergic poisoning also have resulted from belladonna alkaloid contaminants in foods, including commercially purchased Paraguay tea (an herbal tea derived from Ilex paraguariensis), hamburger, honey,[9] stiff porridge made from contaminated millet, and homemade "moon flower" wine. Other accidental ingestions include misuse as an edible wild vegetable[10] and inclusion in homemade toothpaste,[11] as well as a large epidemic in New York and the eastern US that resulted from heroin contaminated with scopolamine[12] .
Although most tropane alkaloids cause an anticholinergic syndrome, a case report indicates that the tropane alkaloid–containing medicinal herb Erycibe henri Prain ("Ting Kung Teng") contains a tropane alkaloid that may cause a cholinergic syndrome, as well as renal, hepatic, and erythrocyte toxicity.[13] This is considered atypical for the tropane alkaloids, which are predominantly strongly anticholinergic.
See 11 Common Plants That Can Cause Dangerous Poisonings, a Critical Images slideshow, to help identify plant reactions and poisonings.
For patient education information, see the First Aid Center as well as Poisoning Treatment.
Toxicity from plants containing tropane alkaloids manifests as classic anticholinergic poisoning. Symptoms usually occur 30-60 minutes after ingestion and may continue for 24-48 hours because tropane alkaloids delay gastric emptying and absorption.
Scopolamine, acting as an antagonist at both peripheral and central muscarinic receptors, is thought to be the primary compound responsible for the toxic effects of these plants. Tropane alkaloids are found in all parts of the plants, with highest concentrations in roots and seeds.
Atropine is an artifact of purification, produced by racemization of l-hyoscyamine. The proportion of each alkaloid present varies among species, time of year, location, and part of plant. As little as one-half teaspoon of Datura seed, equivalent to 0.1 mg of atropine per seed, has caused death from cardiopulmonary arrest. The usual route of ingestion is as a tea, although ingesting seeds or other plant parts and smoking dried leaves also are common.
Incidence is sporadic, with clusters of poisoning cases, mostly among adolescents using plants for their hallucinogenic effects.
According to the American Association of Poison Control Centers' National Poison Data System Annual Report, 528 single exposures to anticholinergic plants were reported in 2017; 107 of those were treated in health care facilities. Major outcomes occurred in four cases, but no deaths were documented.[14]
During 1998-2004, a total of 188 reported human exposures were identified by Texas Poison Control Centers.[15] Seventy-six percent of the exposures occurred in June-October, 82% of the cases occurred in males, and 72% of cases occurred in those aged 13-19 years.
Widespread access to information on hallucinogenic plants through the Internet may lead to a further increase in the incidence.
Worldwide incidence is unknown. However, cases have been reported in Germany, Italy, Greece, Saudi Arabia, Tanzania, Australia, Brazil, Hong Kong, Taiwan, Mexico, Chile, and Venezuela, attesting to broad geographic distribution of Datura species.
Males are more frequently involved in cases of intentional exposure.
No age predilection exists, although Datura use as a recreational drug is more common among adolescents. Accidental ingestion and resultant toxicity in children has been reported.
Nonfatal cases are likely underreported. Reports of sporadic cases or clusters of cases involving intentional use as a hallucinogen are frequent; most patients recover uneventfully, although fatalities do occur.[16]
Of the 528 anticholinergic plant poisonings reported to the American Association of Poison Control Centers in 2017, none proved fatal.[14] Related deaths from drowning, exposure, and lack of supportive care have been reported.
In 1993, 318 cases of Datura poisoning were reported to the American Association of Poison Control Centers; the Centers for Disease Control and Prevention (CDC) reported two deaths. In 1994, the CDC reported seven cases of anticholinergic poisoning in three families who consumed contaminated commercial Paraguay tea.[17]
As in any patient presenting with an acute change in mental status or suspected poisoning, attempt to obtain the following information:
Complete past medical history
Medication history
Precise description or sample of suspected toxicant(s)
Route of administration, amount ingested, time since ingestion, and reason for ingestion
Co-ingestants and use of alcohol or other street drugs
Initial signs and symptoms may include the following:
Dry mucous membranes and skin
Dysphagia and dysarthria
Photophobia
Blurred vision
Tachycardia
Urinary retention
Initial signs and symptoms may be followed by hyperthermia, confusion, agitation, combativeness, seizures, coma, and death. Amnesia regarding events following ingestion of tropane alkaloids is common.
Identification of ingested plants can be diagnostic of tropane alkaloid poisoning. Datura species, the most commonly encountered plants containing tropane alkaloids, are 3-5 foot annuals with coarse-toothed leaves. Trumpet-shaped flowers are 3-5 inches in length, with white-pale-violet colored petals (see the images below).
The mnemonic "red as a beet, dry as a bone, blind as a bat, mad as a hatter, and hot as a hare" is useful for remembering the anticholinergic toxidrome.
Vital signs may include the following:
Tachycardia and tachypnea
Hyperpyrexia (in about 20% of cases)
Inconsistent hypertension and hypotension, respiratory depression (rare)
Warm dry skin (may be flushed)
Head, ears, eyes, nose, and throat findings include mydriasis and cycloplegia (almost always occur and may persist for days) and dry mucous membranes. Diminished bowel sounds and distention of urinary bladder may be present. Neurologic findings include the following:
No specific diagnostic studies for tropane alkaloid poisonings exist. Tropane alkaloids are not included in standard drugs of abuse or comprehensive toxicology panels; serum drug concentrations are neither helpful nor readily available to aid in initial management.
Since acetaminophen and salicylate are common co-ingestants in many poisonings, consider assays for acetaminophen and salicylate levels. In febrile patients, consider blood and urine cultures. Serum electrolyte levels may provide insight into other intoxicating agents and co-ingestants.
Consider a pregnancy test for all female patients of childbearing age.
Consider CT scan of the head for patients with altered mental status that is inadequately explained by toxicity from ingested agent or is unresponsive to appropriate intervention.
Transport patient to the nearest emergency facility with capabilities for advanced life support (ALS), at minimum. Primary assessment should focus on airway and respiratory, circulatory, and neurologic systems. Unless the patient is extremely agitated, obtain intravenous access and monitor vital signs frequently.
Consider administration of naloxone and thiamine. Defer administration of activated charcoal, unless a prolonged transport time is anticipated. Assess for hypoglycemia and other causes of altered mental status. Manage seizures with benzodiazepines. Physostigmine is not recommended in the prehospital setting.
As in all cases of suspected poisoning, follow the ABCDEs of emergency medicine (airway, breathing, circulation, disability, exposure), then the ABCDEs of toxicology (antidotes, basics, change absorption, change distribution, change elimination).
Provide oxygen and intubate if significant CNS or respiratory depression exists and no gag reflex is present. Assess circulation and initiate cardiac and pulse oximetry monitoring. Obtain a 12-lead ECG and evaluate for QRS prolongation, ischemia, and evidence of arrhythmia.
Sinus tachycardia is common and does not require treatment in a stable patient. Obtain blood for laboratory analysis and bedside glucose measurement while obtaining IV access. Inspection after full-body exposure should be performed to assess for signs of trauma or seizure.
Agitated or hallucinating patients often respond to reassurance and a darkened room. If chemical restraint is required, benzodiazepines are the drugs of choice. Early consultation with a poison control center is frequently helpful.
Consider GI decontamination foremost. Ipecac is contraindicated because of the potential for seizures. Gastric lavage is controversial; while it is commonly performed, no reliable data on outcomes exist to support its use, and the risk of aspiration and other complications is increased. Administer activated charcoal (1-2 g/kg) orally or per nasogastric or orogastric tube. One or 2 additional doses may be given at 1- or 2-hour intervals to ensure adequate gut decontamination.
Ileus without distension is not a contraindication to a single dose of charcoal, and charcoal given alone may be as effective or more effective than emesis and lavage procedures. Use of cathartics to hasten elimination from the GI tract remains controversial. Sorbitol may be used with a first dose of charcoal; further use may cause serious fluid shifts to the intestine, diarrhea, dehydration, and hypernatremia.
Tropane alkaloids are lipophilic and cross the blood-brain barrier; hemodialysis and hemoperfusion are generally ineffective. No effective methods of changing distribution or elimination of tropane alkaloids exist.
The specific antidote for tropane alkaloid toxicity is physostigmine salicylate, a reversible acetylcholinesterase inhibitor capable of directly antagonizing CNS manifestations of anticholinergic toxicity. Physostigmine (at doses lower than those producing peripheral side effects of salivation, lacrimation, urination, defecation, emesis) can reverse central anticholinergic effects such as coma, seizures, agitation, and severe dyskinesias.
However, unless relative certainty can be established that the toxicity present is due to tropane alkaloid poisoning and not to co-ingestants or other substances, confirmatory peripheral manifestations of anticholinergic toxicity should coexist prior to administration of physostigmine.
Physostigmine has been used as a diagnostic tool for tropane alkaloid poisoning, but this use is controversial.
Physostigmine can induce a life-threatening cholinergic crisis (eg, seizures, bronchospasm, asystole). Since most patients can be safely treated without this antidote, physostigmine preferably should be used in consultation with a poison control center and generally should be used only for patients in the following states:
Unresponsive to supportive measures
Tachydysrhythmias and subsequent hemodynamic compromise
Intractable seizures unresponsive to benzodiazepines
Extremely severe agitation or psychosis
Physostigmine is contraindicated in patients receiving tricyclic antidepressants, disopyramide, quinidine, procainamide, cocaine, or other agents producing cardiac conduction abnormalities. Relative contraindications include reactive airway disease, intestinal obstruction, and administration of depolarizing paralytic agents.
Following GI decontamination, most patients rarely require more than physiologic monitoring and psychological support. Patients experiencing agitation and hallucinations usually respond to reassurance and benzodiazepines. Most phenothiazines are contraindicated because of their anticholinergic properties. If signs or symptoms of urinary retention exist, Foley catheterization should be performed for bladder decompression.
Base admission decisions on patient's signs and symptoms. Admit symptomatic patients to an ICU setting for monitoring and treatment. They may be discharged after a symptom-free period of 6 hours without use of supportive therapy or antidotes and after appropriate consultations and follow-up have been arranged.
Asymptomatic patients without signs of anticholinergic toxicity or altered mental status may be discharged after 6 hours of observation.
Early consultation with a toxicologist or poison control center is frequently useful for toxic exposures or ingestions to help in decision-making with regard to decontamination and therapeutic interventions. This is particularly true with the use of physostigmine in cases of tropane alkaloid poisoning.
Psychiatric consultation is important for all intentional ingestions. Contact with the patient's primary care provider is optimal for all hospital admissions or cases of serious illness.
Activated charcoal is indicated for all tropane alkaloid poisonings, within an hour of ingestion, with the possible exception of poisoning from smoking leaves. Benzodiazepines are first-line agents for agitation and seizures. Physostigmine should be used only for life-threatening complications.
Clinical Context:
Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. An extremely important component of tropane alkaloid poisoning. May decrease severity and duration of poisoning. Does not dissolve in water.
For maximum effect, administer within 30 min after ingesting poison.
Activated charcoal is used after a drug or plant ingestion to limit adsorption of toxins. Traditionally given after the stomach has been emptied by emesis or lavage, recent evidence indicates that it may be used alone, without lavage.
Clinical Context:
Sedative hypnotic with short onset of effects and relatively long half-life. DOC if IV access is available.
Increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Monitoring patient's blood pressure after administering dose is important. Adjust prn.
Clinical Context:
Used as alternative in termination of refractory status epilepticus. Because midazolam is water soluble, it takes approximately 3 times longer than diazepam to peak EEG effects. Thus clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Published reports of IM and anecdotal reports of nasal use exist (when IV access is not possible).
Clinical Context:
Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Frequently used in prehospital systems since refrigeration is not required.
First-line agents for treatment of tropane-alkaloid-induced seizures. Lorazepam is thought to be most effective and has a longer seizure half-life than diazepam.
Clinical Context:
Reversible anticholinesterase inhibitor that increases the concentration of acetylcholine at cholinergic synapses. The only reversible anticholinesterase inhibitor that readily crosses the blood-brain barrier to produce the desired CNS effects. Some recommend repeated slow IV pushes of 0.1-0.3 mg q3min to a maximum of 2 mg to decrease potential for life-threatening cardiovascular adverse effects.
Physostigmine is indicated only for reversal of life-threatening complications of tropane alkaloid poisoning (eg, tachydysrhythmias with hemodynamic compromise, seizures refractory to other therapeutic interventions, and severe agitation or hallucinations unresponsive to other therapy). The decision to use physostigmine ideally should be made in consultation with a toxicologist or poison control center.
Richard A Wagner, MD, PhD, FACEP, FAAEM, Staff Physician, Department of Emergency Medicine, Tucson Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Samuel M Keim, MD, MS, Professor and Chair, Department of Emergency Medicine, University of Arizona College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
Disclosure: Nothing to disclose.
Chief Editor
Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.
Additional Contributors
Michael S Beeson, MD, MBA, FACEP, Professor of Emergency Medicine, Northeastern Ohio Universities College of Medicine and Pharmacy; Attending Faculty, Akron General Medical Center
Disclosure: Nothing to disclose.
Acknowledgements
Michael Hodgman, MD Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare
Michael Hodgman, MD is a member of the following medical societies: American College of Medical Toxicology, American College of Physicians, Medical Society of the State of New York, and Wilderness Medical Society
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